The present invention relates to a system and method for the separation of substantially impurity-free radionuclides. More particularly, the present invention relates to a system and method for the separation of a solution of a substantially impurity-free solution containing daughter radionuclides from a solution containing the daughter radionuclide and parent radionuclides.
Radioactive materials have a variety of uses including, for example, medical applications in radiodiagnostics and radiotherapeutics. For example, alpha and beta emitting radionuclides have been found to be effective in the treatment and eradication of microscopic disease. Examples of such radionuclides, include, for example, yttrium-90, bismuth-212 and -213, and rhenium-188. The efficacy of such treatments is believed to be a result of the densely ionizing radiation that is emitted during decay.
It has been shown that lead-212 (Pb-212), astatine-211 (At-211), bismuth-212 (Bi-212), bismuth-213 (Bi-213), and yttrium-90 (Y-90) are effective in the treatment and eradication of microscopic carcinoma. In some cases, known methods for producing such alpha or beta particle emitting nuclides are limited in that they generally require the use of particle accelerators or nuclear reactors for their production. Moreover, the radionuclides are often contaminated with impurities, both chemical and radiochemical, that are difficult to filter out or otherwise remove from the desired nuclide.
It has also been found that such nuclides contaminated with impurities do not have the desired property of even distribution to the affected area after administration. Further, the desired radionuclide material and the parent materials emit harmful radiation, exposing the user to great danger. Convenient methods for the separation of Bi-212 and Bi-213 from parental streams have recently been patented. See, Horwitz et al. U.S. Pat. No. 5,854,968 and Rotmensch et al. U.S. Pat. No. 6,126,909, the disclosures of which are incorporated herein by reference.
Moreover, many alpha and beta emitting isotopes have short half-lives. For example, Bi-213 has a half-life of about 45.6 minutes and ultimately decays to stable Bi-209. Therefore, it would be most desirable to produce the desired isotope at a location remote from a particle accelerator or other source, and as physically close to the clinical environment as possible.
Radionuclides can also be used for body imaging or radiodiagnostic purposes to determine the presence of a harmful disease, such as a carcinoma, in an early stage so the disease can be treated early, thus increasing the chance of successful treatment. The radionuclides technetium-99m, thallium-201, fluorine-18, or indium-111, for example, can be used for radiodiagnostic purposes.
Some of these desired radionuclides are xe2x80x9cgrownxe2x80x9d from parent radionuclides. That is, the parent radionuclide is stored for a predetermined period of time to permit the parent to produce the desired daughter radionuclide through radioactive decay. The daughter product must then be separated from the parent as well as any other contaminants that may be present. These processes are typically carried out in solution.
Of importance in the preparation of these, as well as other radionuclides, is the effort to reduce the radiation exposure to the operator, as well as others that are in the general vicinity of the xe2x80x9cgrowingxe2x80x9d and separation processes. Although the daughter products may be alpha-emitting particles, and as such are less problematic to shield, the parent radionuclide, as well as granddaughter products and other possibly present radionuclides can be gamma- and beta-emitters. As such, these xe2x80x9cgrowingxe2x80x9d and separation systems should be well shielded and contained.
The principle of minimizing radiation exposure to all persons is well-known and accepted as the principle of xe2x80x9cAs Low As Reasonably Achievablexe2x80x9d or ALARA. ALARA principles and objectives are adopted in the handling and use of all radioactive materials.
U.S. Pat. No. 6,153,154 (xe2x80x98154 patentxe2x80x99) discloses a method of separating Bi-213 from an Ac-225 (actinium-225) parent solution. However, the method disclosed has many disadvantages including the usage of gas during separation, the possible loss of precious parent solution, and inadequate purification of the daughter, among other disadvantages.
Accordingly, there is a need for a method and system for the production of substantially impurity-free radionuclides in a localized, contained manner, and for a method and system that does not have some or all of the disadvantages the method of the 154 patent has. Desirably, such an apparatus is sufficiently portable so that it can be transported to a patient for administration and treatment without special facilities. Further, such a system and method minimizes an operator""s exposure to harmful radiation.
Chemical purity is vital to a safe and efficient medical procedure because the radionuclide is generally conjugated to a biolocalization agent prior to use. This conjugation reaction relies on the principles of coordination chemistry wherein a radionuclide is chelated to a ligand that is covalently attached to the biolocalization agent. In a chemically impure sample, the presence of ionic impurities can interfere with this conjugation reaction. If sufficient 99mTc, for example, is not coupled to a given biolocalization agent, poorly defined images are obtained due to insufficient photon density localized at the target site and/or from an elevated in vivo background due to aspecific distribution in the blood pool or surrounding tissues.
Regulation of radionuclidic purity stems from the hazards associated with the introduction of long-lived or high energy radioactive impurities into a patient, especially if the biolocalization and body clearance characteristics of the radioactive impurities are unknown. Radionuclidic impurities pose the greatest threat to patient welfare, and such impurities are the primary focus of clinical quality control measures that attempt to prevent the administration of harmful and potentially fatal doses of radiation to the patient.
The use of radiation in disease treatment has long been practiced, with the mainstay external beam radiation therapy now giving way to more targeted delivery mechanisms such as radioimmunotherapy (RIT), which employs radionuclide conjugation to peptides, proteins, or antibodies that selectively concentrate at the disease site whereby radioactive decay imparts cytotoxic effects. Radioimmunotherapy represents the most selective means of delivering a cytotoxic dose of radiation to diseased cells while sparing healthy tissue. (See, Whitlock, Ind. Eng. Chem. Res. (2000), 39:3135-3139; Hassfjell et al., Chem. Rev. (2001) 101:2019-2036; Imam, J. Radiation Oncology Biol. Phys. (2001) 51:271-278; and McDevitt et al., Science (2001) 294:1537-1540.)
Candidate radionuclides for RIT typically have radioactive half-lives in the range of 30 minutes to several days, coordination chemistry that permits attachment to biolocalization agents, and a high linear energy transfer (LET). The LET is defined as the energy deposited in matter per unit pathlength of a charged particle, (see, Choppin et al., J. Nuclear Chemistry: Theory and Applications; Pergamon Press: Oxford, 1980) and the LET of alpha particles is substantially greater than beta particles. By example, alpha particles having a mean energy in the 5-9 MeV range typically expend their energy within about 50-90 xcexcm in tissue, which corresponds to several cell diameters. The lower LET betaxe2x88x92 particles having energies of about 0.5-2.5 MeV may travel up to 10,000 xcexcm in tissue, and the low LET of these betaxe2x88x92 emissions requires as many as 100,000 decays at the cell surface to afford a 99.99% cell-kill probability. For a single alpha particle at the cellular surface, however, the considerably higher LET provides a 20-40% probability of inducing cell death as the lone alpha particle traverses the nucleus. (See, Hassfjell et al., Chem. Rev. (2001) 101:2019-2036.)
Unfortunately, the LET that makes alpha and betaxe2x88x92 emitting nuclides potent cytotoxic agents for cancer therapy also introduces many unique challenges into the production and purification of these radionuclides for use in medical applications. Foremost among these challenges is the radiolytic degradation of the support material that occurs when the conventional generator methodology is used with high LET radionuclides. (See, Hassfjell et al., Chem. Rev. (2001) 101:2019-2036; Gansow et al., In Radionuclide Generators: New Systems for Nuclear Medicine Applications; Knapp et al. Eds., American Chemical Society: Washington, D.C. (1984) pp 215-227; Knapp, et al. Eds., Radionuclide Generators: New Systems for Nuclear Medicine Applications American Chemical Society: Washington, D.C. (1984) Vol. 241; Dietz et al., Appl. Radiat. Isot. (1992) 43:1093-1101; Mirzadeh et al., J. Radioanal. Nucl. Chem. (1996) 203:471-488; Lambrecht et al., Radiochim. Acta (1997) 77:103-123; and Wu et al., Radiochim. Acta (1997) 79:141-144.)
Radiolytic degradation of the generator support material can result in: (a) diminished chemical purity (e.g., radiolysis products from the support matrix can contaminate the daughter solution); (b) compromised radionuclidic purity (e.g., the support material can release parent radionuclides to the eluate: termed xe2x80x9cbreakthroughxe2x80x9d); (c) diminished yields of daughter radionuclides (e.g., alpha-recoil can force the parent radionuclides into stagnant regions of the support making their decay products less accessible to the stripping eluent); (d) decreases in column flow rates (e.g., fragmentation of the support matrix creates particulates that increase the pressure drop across the column); and (e) erratic performance (e.g., variability in product purity, nonreproducible yields, fluctuating flow rates, etc.). In order to minimize the adverse effects of radiolytic degradation on the chemical and radionuclidic purity of the product, the separation columns may be used a single time so that radiolytic degradation products do not accumulate and interfere with subsequent purification procedures. However, certain applications may allow for multiple uses. Thus, a convenient means of inserting the separation columns into the device and removing them after use is desirable.